The proposed research concerns the electrophysiological and pharmacological investigations of the interactions of several neurotransmitters and neuromodulators which are released at or are present in autonomic ganglia and the mechanisms by which the interactions of these endogenous substances modify the primary nicotinic transmission pathway as well as the secondary pathways. Three types of modulatory mechanisms have been identified, and will be investigated by intracellular or extracellular (sucrose-gap) recording methods, on isolated sympathetic ganglia of the rabbit, rat, guinea pig and bullfrog. First, the intrasynaptic mechanisms which involve postsynaptic, muscarinic, adrenergic, and non-cholinergic receptors, generating the slow epsp, slow ipsp and late slow epsp, respectively, will be investigated. The role of cyclic nucleotides in the generation or modulation of the slow synaptic potentials will be studied. Second, the intersynaptic mechanisms will be evaluated; these mechanisms may involve two major components, the Small Intensely Fluorescent (SIF) cells and inter-neuronal connections. The functional relationships between SIF cells and principal ganglionic neurons, in particular, the role of SIF cells in the generation of slow ipsp and in the facilitation of slow epsp, as well as in the presynaptic inhibition of acetylcholine release, will be investigated. The nature of response and the transmitter responsible for the inter-neuronal communication between principal neurons will be explored. Some of the proposed experiments will be carried out on thin slices of sympathetic ganglia viewed by means of differential interference contrast optics; electrical activities will be monitored simultaneously from the SIF cell and neighboring principal neuron or from two adjacent principal neurons by inserting microelectrodes into the cells in question. The third type of modulatory influences concerns endogenous peptides, i.e., substance P, somatostatin, and enkephalins, which are present in the sympathetic ganglia. The site and ionic mechanisms of actions of these peptides will be studied. Finally, applied aspects of modulatory mechanism, namely the role of SIE cells in regulating impulse transmission, will be studied in the sympathetic ganglia of spontaneously hypertensive rats.